Mechanisms regulating the atherogenic activities of serum amyloid A

急性期血清淀粉样蛋白A(SAA)不仅可以预测心血管疾病事件(CVD)，而且还可以 在动脉粥样硬化的发展中起因果作用。SAA是一个分泌蛋白家族，其 在之前的全身炎症反应中，血浆中的浓度增加了1000倍或更多 回到了几乎检测不到的水平。然而，在慢性炎症性疾病中，SAA也持续升高 如糖尿病、肥胖症、类风湿性关节炎等，而肝脏是SAA的主要来源 在急性炎症反应期间，也有肝外表达的记录。最值得注意的是， 脂肪组织被认为是肥胖人群全身性SAA的重要来源。它已经被公认为 几十年来，血浆SAA水平预测人类患心血管疾病的风险。最近，我们的团队 确定SAA在载脂蛋白E缺陷小鼠的动脉粥样硬化中起致病作用。据无数人说 多个实验室的报告称，SAA在体外发挥了无数的作用，预计会加剧 体内炎症和动脉粥样硬化。然而，这些已发表的研究大多研究了无脂SAA， 忽略了在循环中没有检测到无脂SAA的事实。在大多数情况下，血浆SAA是 发现与高密度脂蛋白(HDL)部分有关，而且越来越多的证据表明 这种高密度脂蛋白抑制了SAA的促炎活性。因此，高密度脂蛋白的一个功能可能是隔离和 中和SAA，限制炎症在体内的传播。值得注意的是，在apoB上也可以检测到SAA 颗粒物，特别是在心血管疾病风险增加的人群中。尽管 SAA与非高密度脂蛋白相关的病理生理学意义尚不清楚，我们已经 研究表明，含有载脂蛋白B的脂蛋白上的SAA增加了它们的蛋白多糖结合，这可能导致 血管滞留增加。综上所述，这些观察结果导致我们提出，支持- SAA的炎症/促动脉粥样硬化活性受影响平衡的因素调节 高密度脂蛋白-SAA、极低密度脂蛋白/低密度脂蛋白-SAA和无脂SAA。为了检验这一假设， 我们已经开发了关键的研究工具，包括具有可诱导的、组织特异性SAA的新型小鼠模型 表达，以达到三个全面和互动的目的：目的1)确定是否高密度脂蛋白重塑 因素(例如，胆固醇酯转移蛋白、磷脂酶A2和氧化)导致释放 来自SAA丰富的高密度脂蛋白的生物活性SAA；目的2)确定SAA与载脂蛋白B的相关性 脂蛋白在体外和体内增加了其致动脉粥样硬化的能力；目的3)确定SAA的组织来源 (肝脏和脂肪组织)在体内影响其脂蛋白分布和/或其促动脉粥样硬化作用。这个 这项提案的结果将证实SAA作为心血管疾病的治疗靶点，并将开发 SAA脂蛋白分布可作为潜在的风险生物标志物。

Acute phase serum amyloid A (SAA) is not only predictive of cardiovascular disease events (CVD) but also plays a causal role in the development of atherosclerosis. SAA is a family of secreted proteins whose concentration in the plasma increases 1000-fold or more during a systemic inflammatory response before returning to near undetectable levels. However, SAA is also persistently elevated in chronic inflammatory conditions such as diabetes, obesity, rheumatoid arthritis, etc. While the liver is the major source of SAA during an acute inflammatory response, extra-hepatic expression has also been documented. Most notably, adipose tissue is thought to be an important source of systemic SAA in obese humans. It has been recognized for decades that plasma levels of SAA predict cardiovascular risk in humans. More recently, our group determined that SAA plays a causative role in atherosclerosis in apoE-deficient mice. According to numerous reports by multiple laboratories, SAA exerts a myriad of effects in vitro that would be expected to exacerbate inflammation and atherosclerosis in vivo. However, most of these published studies investigated lipid-free SAA, overlooking the fact that lipid-free SAA is not detected in the circulation. In most circumstances, plasma SAA is found associated with the high-density lipoprotein (HDL) fraction, and accumulating evidence demonstrates that HDL inhibits SAA’s pro-inflammatory activity. Thus, one function of HDL may be to sequester and neutralize SAA and limit the propagation of inflammation in vivo. Notably, SAA can also be detected on apoB particles, particularly in human populations with increased risk for cardiovascular disease. Although the pathophysiological significance of the association of SAA with non-HDL lipoproteins is not known, we have shown that SAA on apoB-containing lipoproteins augments their proteoglycan binding, which could lead to increased vascular retention. Taken together, these observations lead us to propose that the pro- inflammatory/pro-atherogenic activities of SAA are regulated by factors that influence the equilibrium between HDL-SAA, very low-density lipoprotein/low-density lipoprotein-SAA, and lipid-free SAA. To test this hypothesis, we have developed critical research tools, including novel mouse models with inducible, tissue-specific SAA expression, to achieve three comprehensive and interactive aims: Aim 1) Determine whether HDL remodeling factors (e.g., cholesterol ester transfer protein, phospholipase A2 and oxidation) leads to the release of bioactive SAA from SAA-enriched HDL; Aim 2) Determine whether the association of SAA on apoB lipoproteins increases their atherogenicity in vitro and in vivo; and Aim 3) Determine if the tissue source of SAA (liver versus adipose tissue) influences its lipoprotein distribution and/or its pro-atherogenic effects in vivo. The results of this proposal will validate SAA as a therapeutic target in cardiovascular disease, and will develop SAA lipoprotein distribution as a potential biomarker of risk.